Publications by authors named "Armando Lopez-Guillermo"

210 Publications

Genetic and Phenotypic Attributes of Splenic Marginal Zone Lymphoma.

Blood 2021 Oct 15. Epub 2021 Oct 15.

University of Milan & Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter, international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor meta-data and in genetically modified mouse models, and determined correlations with outcome data. We identified two prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcome, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated two basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.
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http://dx.doi.org/10.1182/blood.2021012386DOI Listing
October 2021

Revised International Prognostic Index and genetic alterations are associated with early failure to R-CHOP in patients with diffuse large B-cell lymphoma.

Br J Haematol 2021 Oct 10. Epub 2021 Oct 10.

Department of Hematology, Hospital Clínic, Barcelona, Spain.

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) cases have a poor outcome. Here we analysed clinico-biological features in 373 DLBCL patients homogeneously treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP), in order to identify variables associated with early failure to treatment (EF), defined as primary refractoriness or relapse within 12 months from diagnosis. In addition to clinical features, mutational status of 106 genes was studied by targeted next-generation sequencing in 111 cases, copy number alterations in 87, and gene expression profile (GEP) in 39. Ninety-seven cases (26%) were identified as EF and showed significantly shorter overall survival (OS). Patients with B symptoms, advanced stage, high levels of serum lactate dehydrogenase (LDH) or β2-microglobulin, low lymphocyte/monocyte ratio and higher Revised International Prognostic Index (R-IPI) scores, as well as those with BCL2 rearrangements more frequently showed EF, with R-IPI being the most important in logistic regression. Mutations in NOTCH2, gains in 5p15·33 (TERT), 12q13 (CDK2), 12q14·1 (CDK4) and 12q15 (MDM2) showed predictive importance for EF independently from R-IPI. GEP studies showed that EF cases were significantly enriched in sets related to cell cycle regulation and inflammatory response, while cases in response showed over-representation of gene sets related to extra-cellular matrix and tumour microenvironment.
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http://dx.doi.org/10.1111/bjh.17858DOI Listing
October 2021

Severe infections in patients with lymphoproliferative diseases treated with new targeted drugs: A multicentric real-world study.

Cancer Med 2021 Sep 23. Epub 2021 Sep 23.

Hematology Department, Hospital Universitario Infanta Leonor, Madrid, Spain.

Background: Lymphoid neoplasms treatment has recently been renewed to increase antitumor efficacy and conventional chemotherapies toxicities. Limited data have been published about the infection risk associated with these new drugs, therefore this study analyzes the infectious complications in patients with lymphoproliferative diseases (LPD) treated with monoclonal antibodies (obinutuzumab, ofatumumab, brentuximab, nivolumab, or pembrolizumab), BTK inhibitors (ibrutinib and acalabrutinib), PI3K inhibitors (idelalisib) and BCL2 inhibitors (venetoclax).

Methods: Multicenter retrospective study of 458 LPD patients treated with targeted therapies in real-life setting, in 18 Spanish institutions, from the time of their commercial availability to August 2020.

Results: Severe infections incidence was 23% during 17-month median follow-up; cumulative incidence was higher in the first 3-6 months of targeted drug treatment and then decreased. The most frequent etiology was bacterial (54%). Nine (6%) Invasive fungal infections (IFI) were observed, in its majority in chronic lymphocytic leukemia (CLL) patients treated predominantly with ibrutinib. Significant risk factors for severe infection were: severe lymphopenia (p = 0.009, OR 4.7, range 1.3-1.7), combined targeted treatment vs single agent treatment (p = 0.014 OR 2.2 range 1.1-4.2) and previous rituximab (p = 0.03 OR 1.8, range 1.05-3.3). Infection-related mortality was 6%. In 22% of patients with severe infections, definitive discontinuation of the targeted drug was observed.

Conclusion: A high proportion of patients presented severe infections during follow-up, with non-negligible attributable mortality, but infection incidence is not superior to the one observed during the chemotherapy era. In selected cases with specific risk factors for infection, antimicrobial prophylaxis should be considered.
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http://dx.doi.org/10.1002/cam4.4293DOI Listing
September 2021

Clinico-biological features and outcome of patients with splenic marginal zone lymphoma with histological transformation.

Br J Haematol 2021 Sep 14. Epub 2021 Sep 14.

Hematology Department and Hematopathology Section, Pathology Department, Hospital Clínic of Barcelona, Barcelona, Spain.

We describe 36 patients with splenic marginal zone lymphoma (SMZL) with transformation (SMZL-T), including 15 from a series of 84 patients with SMZL diagnosed at the Hospital Clinic of Barcelona (HCB) and 21 diagnosed with SMZL-T in other centres. In the HCB cohort, the cumulative incidence of transformation at 5 years was 15%. Predictors for transformation were cytopenias, hypoalbuminaemia, complex karyotype (CK) and both the Intergruppo Italiano Linfomi (ILL) and simplified Haemoglobin, Platelet count, lactate dehydrogenase (LDH) and extrahilar Lymphadenopathy (HPLL)/ABC scores (P < 0·05). The only independent predictor for transformation in multivariate analysis was CK [hazard ratio (HR) 4·025, P = 0·05]. Patients with SMZL-T had a significantly higher risk of death than the remainder (HR 3·89, P < 0·001). Of the 36 patients with SMZL-T, one developed Hodgkin lymphoma and 35 a diffuse large B-cell lymphoma, 71% with a non-germinal centre phenotype. The main features were B symptoms, lymphadenopathy, and high serum LDH. CK was observed in 12/22 (55%) SMZL-T and fluorescence in situ hybridisation detected abnormalities of MYC proto-oncogene, basic helix-loop-helix transcription factor (MYC), B-cell leukaemia/lymphoma 2 (BCL2) and/or BCL6 in six of 14 (43%). In all, 21 patients received immunochemotherapy, six chemotherapy, one radiotherapy and three splenectomy. The complete response (CR) rate was 61% and the median survival from transformation was 4·92 years. Predictors for a worse survival in multivariate analysis were high-risk International Prognostic Index (HR 5·294, P = 0·016) and lack of CR (HR 2·67, P < 0·001).
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http://dx.doi.org/10.1111/bjh.17815DOI Listing
September 2021

Prognostic ability of five clinical risk scores in follicular lymphoma: A single-center evaluation.

Hematol Oncol 2021 Sep 7. Epub 2021 Sep 7.

Department of Hematology, Hospital Clínic de Barcelona, Barcelona, Spain.

With the intention of identifying follicular lymphoma (FL) patients at higher risk of progression, early relapse (POD24), histological transformation (HT) or death, multiple risk scores (RS) have been proposed. However, it has not yet been established whether any of them globally outperforms the others. We evaluated the clinical utility and statistical performance of the five most widely used clinical scores (IPI, ILI, FLIPI, FLIPI2, PRIMA-PI) in a single-center series of 414 grade 1-3A FL patients diagnosed in the rituximab era. Overall concordance (proportion of patients allocated to the same risk category by all five RS) was 24%. FLIPI and FLIPI2 were predictive of time to first treatment. All five scores were predictive of response, POD24, progression-free, and OS, while only FLIPI predicted HT. IPI identified a small subset (7%) of truly high-risk patients (10-year OS of 16%). In subgroup analyses, we showed that ILI is useful in the prognostication of limited-disease patients, and PRIMA-PI is an age-independent score that can identify a high-risk subset of older patients. Performance metrics were slightly better for IPI in terms of calibration (Harrell's c-index 0.73), without major differences among RS regarding other parameters. Although the incorporation of molecular and imaging data will continue to refine the stratification of FL patients, FLIPI remains the most powerful clinical prognostic index in the rituximab era, predicting the greatest number of endpoints.
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http://dx.doi.org/10.1002/hon.2922DOI Listing
September 2021

A randomized phase II study comparing consolidation with a single dose of Y ibritumomab tiuxetan maintenance with rituximab for two years in patients with newly diagnosed follicular lymphoma responding to R-CHOP. Long-term follow-up results.

Leuk Lymphoma 2021 Aug 30:1-8. Epub 2021 Aug 30.

Hematology Department, MD Anderson Cancer Center, Madrid, Spain.

This is a randomized phase-2 trial aimed to compare consolidation vs. maintenance in untreated patients with follicular lymphoma (FL) responding to induction. 146 patients were enrolled from 25 Spanish institutions (ZAR2007; ClinicalTrials.gov #NCT00662948). Patients in PR or CR/CR[u] after R-CHOP were randomized 1:1 to Y-ibritumomab-tiuxetan 0.4 mCi/kg (arm A) vs. rituximab 375 mg/m every 8 weeks for 2 years (arm B). After a median follow-up of 10.55 years, 53 patients eventually progressed with a 10-year PFS of 50% vs. 56% for patients in arm A and B, respectively (HR = 1.42;  > 0.1). No significant differences were seen in OS (10-year OS 78% vs. 84.5%; HR = 1.39,  > .1). Patients receiving Y-ibritumomab-tiuxetan showed higher incidence of second neoplasms than those in arm B (10-year cumulative incidence 18.5 vs. 2%, respectively;  = .038). In conclusion, in FL patients responding to R-CHOP, no significant differences were found between consolidation and maintenance, although with higher late toxicity for consolidation.
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http://dx.doi.org/10.1080/10428194.2021.1971216DOI Listing
August 2021

Clinicobiological Characteristics and Outcomes of Patients with T-Cell Large Granular Lymphocytic Leukemia and Chronic Lymphoproliferative Disorder of Natural Killer Cells from a Single Institution.

Cancers (Basel) 2021 Aug 2;13(15). Epub 2021 Aug 2.

Hematopathology Unit, Department of Pathology, Hospital Clínic, 08036 Barcelona, Spain.

T-cell large granular lymphocytic leukemia (T-LGLL) and chronic lymphoproliferative disorder of natural killer (NK) cells are two infrequent diseases characterized by clonal expansions of cytotoxic T lymphocytes and NK cells, respectively. Somatic mutations of are involved in the pathogenesis of these entities. We describe the clinicobiological features, mutational status of , treatment and outcome of 131 patients. Neutropenia was the most frequent finding at diagnosis, followed by anemia. Concurrent hematological disorders were diagnosed in 37% of patients and autoimmune conditions and solid tumors in 17% and 15%, respectively. All patients who needed treatment belonged to the CD8CD57 group. Remarkably, patients included in the CD4 group had a higher association with solid tumors ( = 0.037). mutations were found in 17% of patients, mainly Y640F and D661Y mutations. Patients carrying mutations more frequently presented with anemia, neutropenia, high LDH, high large granular lymphocyte counts and need for treatment ( = 0.0037). Methotrexate was the most frequently used agent (72% of cases). The overall response rate to all treatments was 50%. The 10-year overall survival of this series was 78%, with no differences according to the mutational status of . We compared the survival of these patients with the general Spanish population and no differences were found, confirming the indolent nature of these hematological malignancies. Our study further extends findings documented by others on the clinical behavior of the disease and the impact of , and for the first time analyzes survival compared to a matched general Spanish population.
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http://dx.doi.org/10.3390/cancers13153900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345581PMC
August 2021

Follicular lymphoma: an update on diagnosis, prognosis, and management.

Med Clin (Barc) 2021 Jun 28. Epub 2021 Jun 28.

Servicio de Hematología, Hospital Clínic, Barcelona, España; Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, España.

Follicular lymphoma, the most common indolent lymphoma, originates from germinal centre B-cells of the lymphoid follicle, and is characterized by t(14;18). Clinical manifestations include the presence of lymphadenopathy, sometimes accompanied by constitutional symptoms or cytopenia. Diagnosis is established through the identification of a B-cell proliferation of nodular pattern in the lymph node biopsy. Upon staging with PET-CT and bone marrow biopsy, a significant proportion of patients do not need immediate treatment. When therapy is indicated, commonly used regimens include anti-CD20 immunotherapy with or without chemotherapy. Although overall survival for most patients is prolonged, relapses are very frequent, and early relapse and transformation to an aggressive lymphoma portend a much worse prognosis. New therapies are under development, which will most likely change outcomes for FL patients in the near future.
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http://dx.doi.org/10.1016/j.medcli.2021.03.041DOI Listing
June 2021

SOX11, CD70 and Treg cells configure the tumor immune microenvironment of aggressive mantle cell lymphoma.

Blood 2021 Jun 29. Epub 2021 Jun 29.

IDIBAPS, Barcelona, Spain.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with a heterogeneous clinical and biological behavior. SOX11 oncogenic expression contributes to the aggressiveness of these tumors by different mechanisms including tumor and stromal cell interactions. However, the precise composition of the immune cell microenvironment of MCL, its possible relationship to SOX11 expression, and how it may contribute to tumor behavior is not well known. Here, we performed an integrative transcriptome analysis of 730 immune-related genes combined with the immune cell phenotype analysis by immunohistochemistry in SOX11+ and SOX11- primary nodal MCL cases and non-neoplastic reactive lymph nodes (RLN). SOX11+ MCL had a significant lower T-cell intratumoral infiltration compared to negative cases. A reduced expression of MHCI/II-like and T-cell costimulation and signaling activation related transcripts was significantly associated with poor clinical outcome. Moreover, we identified CD70 as a SOX11 direct target gene, whose overexpression was induced in SOX11+ but not SOX11- tumor cells by CD40L in vitro. CD70 was overexpressed in primary SOX11+ MCL and it was associated with an immune unbalance of the tumor microenvironment characterized by increased number of effector Treg cell infiltration, higher proliferation, and aggressive clinical course. CD27 was expressed with moderate to strong intensity in 76% of cases. Overall, our results suggest that SOX11 expression in MCL is associated with an immunosuppressive microenvironment characterized by CD70 overexpression in tumor cells, increased Treg cell infiltration and downmodulation of antigen-processing and -presentation and T-cell activation that could promote MCL progression and represent a potential target for tailored therapies.
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http://dx.doi.org/10.1182/blood.2020010527DOI Listing
June 2021

Past, present and future of prognostic scores in follicular lymphoma.

Blood Rev 2021 Jun 24:100865. Epub 2021 Jun 24.

Department of Hematology, Hospital Clínic de Barcelona, Barcelona, Spain.

Although most follicular lymphoma (FL) patients have prolonged survival, the identification of those at risk of early progression, multiple relapses or histological transformation is essential for the improvement of long-term outcomes. In this sense, a plethora of prognostic indexes have been developed in the last decades. However, determining which one is more accurate and clinically meaningful remains a challenge. Key factors for the external validity of available indexes include characteristics of the study population, treatment intervention, and design of the study. While initial risk scores were composed of clinical, biochemical, and hematological variables, genomic and imaging data have been incorporated in recent years. Despite an obvious step forward in the knowledge of the natural history and biology of FL, predictions remain inaccurate. Further research will likely incorporate information from circulating tumor DNA and artificial intelligence models to refine the prognostic classification of the heterogeneous FL population.
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http://dx.doi.org/10.1016/j.blre.2021.100865DOI Listing
June 2021

The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome.

Nat Cancer 2020 Nov 2;1(11):1066-1081. Epub 2020 Nov 2.

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

We report a systematic analysis of the DNA methylation variability in 1,595 samples of normal cell subpopulations and 14 tumor subtypes spanning the entire human B-cell lineage. Differential methylation among tumor entities relates to differences in cellular origin and to epigenetic alterations, which allowed us to build an accurate machine learning-based diagnostic algorithm. We identify extensive patient-specific methylation variability in silenced chromatin associated with the proliferative history of normal and neoplastic B cells. Mitotic activity generally leaves both hyper- and hypomethylation imprints, but some B-cell neoplasms preferentially gain or lose DNA methylation. Subsequently, we construct a DNA methylation-based mitotic clock called epiCMIT, whose lapse magnitude represents a strong independent prognostic variable in B-cell tumors and is associated with particular driver genetic alterations. Our findings reveal DNA methylation as a holistic tracer of B-cell tumor developmental history, with implications in the differential diagnosis and prediction of clinical outcome.
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http://dx.doi.org/10.1038/s43018-020-00131-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168619PMC
November 2020

Response to: The lymphocyte-to-monocyte ratio in follicular lymphoma.

Leuk Lymphoma 2021 Oct 1;62(10):2562-2563. Epub 2021 Jun 1.

Department of Hematology, Hospital Clínic de Barcelona, Barcelona, Spain.

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http://dx.doi.org/10.1080/10428194.2021.1933482DOI Listing
October 2021

The receptor of the colony-stimulating factor-1 (CSF-1R) is a novel prognostic factor and therapeutic target in follicular lymphoma.

Leukemia 2021 09 17;35(9):2635-2649. Epub 2021 Mar 17.

Department of Hematology-Oncology, IDIBAPS, Barcelona, Spain.

Microenvironment contributes to follicular lymphoma (FL) pathogenesis and impacts survival with macrophages playing a controversial role. In the present study, using FL primary samples and HK follicular dendritic cells (FDC) to mimic the germinal center, together with mouse models, we have analyzed the three-way crosstalk of FL-FDC-macrophages and derived therapeutic opportunities. Ex vivo primary FL-FDC co-cultures (n = 19) and in vivo mouse co-xenografts demonstrated that FL-FDC crosstalk favors tumor growth and, via the secretion of CCL2 and CSF-1, promotes monocyte recruitment, differentiation, and polarization towards an M2-like protumoral phenotype. Moreover, FL-M2 co-cultures displayed enhanced angiogenesis, dissemination, and immunosuppression. Analysis of the CSF-1/CSF-1R pathway uncovered that CSF-1 was significantly higher in serum from grade 3A FL patients, and that high CSF-1R expression in FL biopsies correlated with grade 3A, reduced overall survival and risk of transformation. Furthermore, CSF-1R inhibition with pexidartinib (PLX3397) preferentially affected M2-macrophage viability and polarization program disrupting FL-M2 positive crosstalk. In vivo CSF1-R inhibition caused M2 reduction and repolarization towards M1 macrophages and antitumor effect cooperating with anti-CD20 rituximab. In summary, these results support the role of macrophages in FL pathogenesis and indicate that CSF-1R may be a relevant prognostic factor and a novel therapeutic target cooperating with anti-CD20 immunotherapy.
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http://dx.doi.org/10.1038/s41375-021-01201-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410584PMC
September 2021

Age and comorbidity are determining factors in the overall and relative survival of patients with follicular lymphoma.

Ann Hematol 2021 May 25;100(5):1231-1239. Epub 2021 Feb 25.

Department of Hematology, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain.

Frailty and concurrent medical conditions are crucial factors in the management of follicular lymphoma (FL). We evaluated the impact of age and comorbidity on survival, causes of death, histological transformation (HT), and second malignancies (SM) in a large single-center series of grade 1-3A FL. We studied 414 patients diagnosed in the rituximab era, categorized into three age groups (≤60, 61-70, >70 years) and two comorbidity groups (Charlson Comorbidity Index, CCI, 0-1 and ≥2). Despite a similar cumulative incidence of relapse, older and comorbid patients had a lower 10-year overall survival (OS, 88, 65, and 41% for patients ≤60 years, 61-70 years, and >70 years, P<0.0001; and 76 vs. 51% for CCI 0-1 and ≥2, P<0.0001). In a multivariate analysis for OS, comorbidity retained its prognostic impact (HR=2.5, P=0.0003). The proportion of patients dying due to FL was higher among those ≤60 years (74%) and those with a CCI 0-1 (67%). Furthermore, 10-year excess mortality (survival reduction) was more prominent for patients >70 years (30%) and those with a CCI ≥2 (32%). Patients with a CCI ≥2 also had a higher incidence of SM. These data encourage a comprehensive pre-treatment evaluation and a tailored therapeutic approach for all FL patients.
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http://dx.doi.org/10.1007/s00277-021-04470-7DOI Listing
May 2021

Baseline correlations and prognostic impact of serum monoclonal proteins in follicular lymphoma.

Br J Haematol 2021 04 16;193(2):299-306. Epub 2020 Nov 16.

Department of Haematology, Hospital Clínic de Barcelona, Barcelona, Spain.

The presence of a serum monoclonal component has been associated with poor outcomes in some lymphomas. However, data in follicular lymphoma (FL) are scarce. We studied 311 FL patients diagnosed at a single institution, for whom information on serum immunofixation electrophoresis (sIFE) at diagnosis was available. Baseline characteristics and outcomes were compared between patients with a positive (+sIFE) and a negative sIFE (-sIFE). sIFE was positive in 82 patients (26%). Baseline features were comparable between both groups, except for an older age and higher proportion of elevated β -microglobulin levels in the +sIFE group. With a median follow-up of 4.6 years, a +sIFE was associated with a higher risk of early relapse (POD24, 27% vs. 15%, P = 0·02), shorter progression-free survival (PFS; 42% vs. 52% at 5 years, P = 0·008), and shorter overall survival (OS; 59% vs. 77% at 10 years, P = 0·046). In patients >60 years, a +sIFE was an independent predictor of OS [hazard ratio (HR) = 2·4, 95% confidence interval (CI): 1·2-5·0; P = 0·02]. Approximately one quarter of patients with FL has a +sIFE at diagnosis, which is a predictor of poor outcome. These findings encourage further investigation of its relationship with B-cell biology and the tumour microenvironment.
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http://dx.doi.org/10.1111/bjh.17138DOI Listing
April 2021

Serum monoclonal component in chronic lymphocytic leukemia: baseline correlations and prognostic impact.

Haematologica 2021 06 1;106(6):1754-1757. Epub 2021 Jun 1.

Department of Hematology, Hospital Clínic, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid.

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http://dx.doi.org/10.3324/haematol.2020.263228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168485PMC
June 2021

Early progression of disease predicts shorter survival in MALT lymphoma patients receiving systemic treatment.

Haematologica 2020 11 1;105(11):2592-2597. Epub 2020 Nov 1.

Division of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.

Early progression of disease (POD) within two years from diagnosis is linked with poor overall survival (OS) in follicular lymphoma but its prognostic role is less clear in extranodal marginal zone B-cell lymphoma (EMZL). We sought to identify prognostic factors associated with early POD and to determine whether is associated with inferior OS. We analyzed the impact of early POD in the IELSG19 clinical trial dataset (training set of 401 patients randomly assigned to chlorambucil or rituximab or chlorambucil plus rituximab). Reproducibility was examined in a validation set of 287 patients who received systemic treatment. In both sets, we excluded from the analysis the patients who, within 24 months from treatment start, died without progression or were lost to follow-up without prior progression. OS was calculated from progression in patients with early POD and from 24 months after start of treatment in those without (reference group). Early POD was observed in 69 of the 384 (18%) evaluable patients of the IELSG19 study. Patients with high-risk MALT-IPI were more likely to have early POD (p=0.006). The 10-year OS rate was 64% in the early POD group and 85% in the reference group (HR= 2.42, 95%CI, 1.35-4.34; log-rank P=0.002). This prognostic impact was confirmed in the validation set, in which early POD was observed in 64 out of 224 (29%) evaluable patients with 10-year OS rate of 48% in the early POD group and 71% in the reference group (HR= 2.15, 95%CI, 1.19-3.90; log-rank P=0.009). In patients with EMZL who received front-line systemic treatment, early POD is associated with poorer survival and may represent a useful endpoint in future prospective clinical trials.
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http://dx.doi.org/10.3324/haematol.2019.237990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604574PMC
November 2020

Mutational Landscape and Tumor Burden Assessed by Cell-free DNA in Diffuse Large B-Cell Lymphoma in a Population-Based Study.

Clin Cancer Res 2021 01 29;27(2):513-521. Epub 2020 Oct 29.

Department of Hematology, Hospital Clínic de Barcelona, Barcelona, Spain.

Purpose: We analyzed the utility of cell-free DNA (cfDNA) in a prospective population-based cohort to determine the mutational profile, assess tumor burden, and estimate its impact in response rate and outcome in patients with diffuse large B-cell lymphoma (DLBCL).

Experimental Design: A total of 100 patients were diagnosed with DLBCL during the study period. Mutational status of 112 genes was studied in cfDNA by targeted next-generation sequencing. Paired formalin-fixed, paraffin-embedded samples and volumetric PET/CT were assessed when available.

Results: Appropriate cfDNA to perform the analyses was obtained in 79 of 100 cases. At least one mutation could be detected in 69 of 79 cases (87%). The sensitivity of cfDNA to detect the mutations was 68% (95% confidence interval, 56.2-78.7). The mutational landscape found in cfDNA samples was highly consistent with that shown in the tissue and allowed genetic classification in 43% of the cases. A higher amount of circulating tumor DNA (ctDNA) significantly correlated with clinical parameters related to tumor burden (elevated lactate dehydrogenase and β2-microglobulin serum levels, advanced stage, and high-risk International Prognostic Index) and total metabolic tumor volume assessed by PET/CT. In patients treated with curative intent, high ctDNA levels (>2.5 log hGE/mL) were associated with lower complete response (65% vs. 96%; < 0.004), shorter progression-free survival (65% vs. 85%; = 0.038), and overall survival (73% vs. 100%; = 0.007) at 2 years, although it did not maintain prognostic value in multivariate analyses.

Conclusions: In a population-based prospective DLBCL series, cfDNA resulted as an alternative source to estimate tumor burden and to determine the tumor mutational profile and genetic classification, which have prognostic implications and may contribute to a future tailored treatment.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2558DOI Listing
January 2021

A Cyclin D1-Dependent Transcriptional Program Predicts Clinical Outcome in Mantle Cell Lymphoma.

Clin Cancer Res 2021 01 12;27(1):213-225. Epub 2020 Oct 12.

Lymphoid Neoplasm Program, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.

Purpose: Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation leading to cyclin D1 overexpression. Cyclin D1 is a major cell-cycle regulator and also regulates transcription, but the impact of cyclin D1-mediated transcriptional dysregulation on MCL pathogenesis remains poorly understood. The aim of this study was to define a cyclin D1-dependent gene expression program and analyze its prognostic value.

Experimental Design: We integrated genome-wide expression analysis of cyclin D1-silenced and overexpressing cells with cyclin D1 chromatin-binding profiles to identify a cyclin D1-dependent transcriptional program in MCL cells. We analyzed this gene program in two MCL series of peripheral blood samples ( = 53) and lymphoid tissues ( = 106) to determine its biological and clinical relevance. We then obtained a simplified signature of this program and evaluated a third series of peripheral blood MCL samples ( = 81) by NanoString gene expression profiling to validate our findings.

Results: We identified a cyclin D1-dependent transcriptional program composed of 295 genes that were mainly involved in cell-cycle control. The cyclin D1-dependent gene program was overexpressed in MCL tumors directly proportional to cyclin D1 levels. High expression of this program conferred an adverse prognosis with significant shorter overall survival of the patients. These observations were validated in an independent cohort of patients using a simplified 37-gene cyclin D1 signature. The cyclin D1-dependent transcriptional program was also present in multiple myeloma and breast tumors with cyclin D1 overexpression.

Conclusions: We identified a cyclin D1-dependent transcriptional program that is overexpressed in MCL and predicts clinical outcome.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051616PMC
January 2021

A low lymphocyte-to-monocyte ratio is an independent predictor of poorer survival and higher risk of histological transformation in follicular lymphoma.

Leuk Lymphoma 2021 01 19;62(1):104-111. Epub 2020 Sep 19.

Department of Hematology, Hospital Clínic de Barcelona, Barcelona, Spain.

The lymphocyte-to-monocyte ratio (LMR) is a prognostic factor in different neoplasms, but its potential importance in follicular lymphoma (FL) is not well defined. We studied 384 FL patients for which the LMR was available at diagnosis. Baseline features and outcomes were compared between patients with an LMR ≤/>2.5. The 76 patients (20%) who had an LMR ≤2.5 were older and had a higher tumor burden. A low LMR was predictive of a lower 10-y progression-free survival (32 vs. 55%,  = .001) and overall survival (35 vs. 78%,  < .0001; HR = 2.3,  = .003 in a 6-element multivariable model). A low LMR was also an independent risk factor for histological transformation (11 vs. 6% at 10 years,  = .01). Likewise, patients with a low LMR had a higher rate of second malignancies. The potential utility of this widely available parameter and its contribution to well-established prognostic scores need to be explored in independent, prospective series.
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http://dx.doi.org/10.1080/10428194.2020.1821010DOI Listing
January 2021

PI3Kδ inhibition reshapes follicular lymphoma-immune microenvironment cross talk and unleashes the activity of venetoclax.

Blood Adv 2020 09;4(17):4217-4231

Department of Hematology-Oncology, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain.

Despite idelalisib approval in relapsed follicular lymphoma (FL), a complete characterization of the immunomodulatory consequences of phosphatidylinositol 3-kinase δ (PI3Kδ) inhibition, biomarkers of response, and potential combinatorial therapies in FL remain to be established. Using ex vivo cocultures of FL patient biopsies and follicular dendritic cells (FDCs) to mimic the germinal center (n = 42), we uncovered that PI3Kδ inhibition interferes with FDC-induced genes related to angiogenesis, extracellular matrix formation, and transendothelial migration in a subset of FL samples, defining an 18-gene signature fingerprint of idelalisib sensitivity. A common hallmark of idelalisib found in all FL cases was its interference with the CD40/CD40L pathway and induced proliferation, together with the downregulation of proteins crucial for B-T-cell synapses, leading to an inefficient cross talk between FL cells and the supportive T-follicular helper cells (TFH). Moreover, idelalisib downmodulates the chemokine CCL22, hampering the recruitment of TFH and immunosupressive T-regulatory cells to the FL niche, leading to a less supportive and tolerogenic immune microenvironment. Finally, using BH3 profiling, we uncovered that FL-FDC and FL-macrophage cocultures augment tumor addiction to BCL-XL and MCL-1 or BFL-1, respectively, limiting the cytotoxic activity of the BCL-2 inhibitor venetoclax. Idelalisib restored FL dependence on BCL-2 and venetoclax activity. In summary, idelalisib exhibits a patient-dependent activity toward angiogenesis and lymphoma dissemination. In all FL cases, idelalisib exerts a general reshaping of the FL immune microenvironment and restores dependence on BCL-2, predisposing FL to cell death, providing a mechanistic rationale for investigating the combination of PI3Kδ inhibitors and venetoclax in clinical trials.
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http://dx.doi.org/10.1182/bloodadvances.2020001584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479943PMC
September 2020

Genomic and epigenomic insights into the origin, pathogenesis, and clinical behavior of mantle cell lymphoma subtypes.

Blood 2020 09;136(12):1419-1432

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm initially driven by CCND1 rearrangement with 2 molecular subtypes, conventional MCL (cMCL) and leukemic non-nodal MCL (nnMCL), that differ in their clinicobiological behavior. To identify the genetic and epigenetic alterations determining this diversity, we used whole-genome (n = 61) and exome (n = 21) sequencing (74% cMCL, 26% nnMCL) combined with transcriptome and DNA methylation profiles in the context of 5 MCL reference epigenomes. We identified that open and active chromatin at the major translocation cluster locus might facilitate the t(11;14)(q13;32), which modifies the 3-dimensional structure of the involved regions. This translocation is mainly acquired in precursor B cells mediated by recombination-activating genes in both MCL subtypes, whereas in 8% of cases the translocation occurs in mature B cells mediated by activation-induced cytidine deaminase. We identified novel recurrent MCL drivers, including CDKN1B, SAMHD1, BCOR, SYNE1, HNRNPH1, SMARCB1, and DAZAP1. Complex structural alterations emerge as a relevant early oncogenic mechanism in MCL, targeting key driver genes. Breakage-fusion-bridge cycles and translocations activated oncogenes (BMI1, MIR17HG, TERT, MYC, and MYCN), generating gene amplifications and remodeling regulatory regions. cMCL carried significant higher numbers of structural variants, copy number alterations, and driver changes than nnMCL, with exclusive alterations of ATM in cMCL, whereas TP53 and TERT alterations were slightly enriched in nnMCL. Several drivers had prognostic impact, but only TP53 and MYC aberrations added value independently of genomic complexity. An increasing genomic complexity, together with the presence of breakage-fusion-bridge cycles and high DNA methylation changes related to the proliferative cell history, defines patients with different clinical evolution.
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http://dx.doi.org/10.1182/blood.2020005289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498364PMC
September 2020

HHV8-positive, EBV-positive Hodgkin lymphoma-like large B cell lymphoma: expanding the spectrum of HHV8 and EBV-associated lymphoproliferative disorders.

Int J Hematol 2020 Nov 11;112(5):734-740. Epub 2020 Jun 11.

Hematopathology Unit, Department of Pathology, Hospital Clinic of Barcelona, Barcelona, Spain.

Human herpesvirus type 8 (HHV8) is a gamma herpesvirus known for its role in lymphoid neoplasms, especially in immunosuppressed patients. We describe the case of a 64-year-old male, without known immunodeficiency, with 1-year-long clinical history of mediastinal and abdominal lymphadenopathies and recurrent pulmonary infections. Histopathological evaluation of a mediastinal lymph node revealed the presence of scattered atypical large cells with Hodgkin and Reed-Sternberg morphology in a background of lymphocytes and extensive areas of fibrosis. The large cells were positive for HHV8 and Epstein-Barr virus (EBV), with a clonal pattern of IGH gene rearrangement. A descriptive diagnosis of "HHV8-positive, EBV-positive Hodgkin lymphoma-like large B-cell lymphoma" was rendered. Interestingly, the retrospective evaluation of a previous biopsy, diagnosed as reactive lymphadenitis, revealed the presence of HHV8- and EBV-positive cells, with a polyclonal pattern and a small peak corresponding to that of the most recent biopsy. This case presents diagnostic challenges due to the presence of particular features not clearly related to current HHV8-associated entities, and also suggests the possibility for disease progression in the spectrum of HHV8- and EBV-associated lymphoproliferative disorders.
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http://dx.doi.org/10.1007/s12185-020-02897-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287409PMC
November 2020

High serum levels of IL-2R, IL-6, and TNF-α are associated with higher tumor burden and poorer outcome of follicular lymphoma patients in the rituximab era.

Leuk Res 2020 07 19;94:106371. Epub 2020 May 19.

Department of Hematology, Hospital Clínic de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain; Universitat de Barcelona, Barcelona, Spain. Electronic address:

The clinical behavior of FL patients is heterogeneous. The levels of sIL-2R have been correlated with tumor burden and outcome in FL. However, the impact of IL-6 and TNF-α in this disease is unclear. We studied 253 patients diagnosed with grade 1-3a FL between 2002 and 2018, with available information on serum levels of sIL-2R, IL-6, and TNF-α at diagnosis. Patients with cytokine levels above the cutoff had features of a higher tumor burden and higher-risk disease. Levels of any of the studied cytokines above the cutoff and a higher number of cytokines above the cutoff impacted on a shorter PFS and OS. TNF-α levels were an independent predictor of a poorer PFS. No differences were observed in the risk of histological transformation or second malignancies. The determination of cytokine levels in FL patients is feasible in clinical practice, and elevated levels are associated with a higher tumor burden and poorer survival.
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http://dx.doi.org/10.1016/j.leukres.2020.106371DOI Listing
July 2020

Patterns of change in treatment, response, and outcome in patients with follicular lymphoma over the last four decades: a single-center experience.

Blood Cancer J 2020 03 5;10(3):31. Epub 2020 Mar 5.

Department of Hematology, Hospital Clínic, Barcelona, Spain.

Although the introduction of immunotherapy has improved outcomes for follicular lymphoma (FL) patients, histological transformation (HT) and early relapse still confer a poor prognosis. We sought to describe the patterns of change in treatment, response, and outcome of FL patients at our institution over the last four decades. Seven hundred and twenty-seven patients (389 F/338 M; median age, 57 years) consecutively diagnosed with grade 1-3a FL between 1980 and 2017, categorized into four decades according to the time of diagnosis, constituted the study population. Clinical characteristics, treatment, response, absolute and relative survival, HT, second malignancies (SM), and causes of death were assessed. Median OS for the entire cohort was 17.6 years. From decade 1 to 4, there was an increase in the complete response rate (48 to 70%), progression-free survival (40 to 56% at 5 years), OS (77 to 86% at 5 years), and relative survival ratio (0.83 to 0.94 at 5 years), with no significant differences in the risk of HT or SM. Lymphoma remained the most common cause of death in all four decades. These findings illustrate the overall improvement in outcome for FL patients, but support the need for further research into risk stratification and management.
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http://dx.doi.org/10.1038/s41408-020-0299-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058022PMC
March 2020

RELINF: prospective epidemiological registry of lymphoid neoplasms in Spain. A project from the GELTAMO group.

Ann Hematol 2020 Apr 20;99(4):799-808. Epub 2020 Feb 20.

Haematology Department, Hospital Dr. Peset, Valencia, Spain.

Lymphomas are a large, heterogeneous group of neoplasms with well-defined characteristics, and this heterogeneity highlights the importance of epidemiological data. Knowledge of local epidemiology is essential to optimise resources, design clinical trials, and identify minority entities. Given there are few published epidemiological data on lymphoma in Spain, the Spanish Lymphoma and Autologous Bone Marrow Transplant Group created the RELINF project. The aim of this project is to determine the frequencies and distribution of lymphoid neoplasms in Spain and to analyse survival. We developed an online platform for the prospective collection of data on newly diagnosed cases of lymphoma in Spain between January 2014 and July 2018; 11,400 patients were registered. Diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) were the most frequent lymphomas in our series. Marginal B cell lymphoma frequency was higher than that reported in other studies, representing more than 11% of mature B cell lymphomas. Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) was the most common subtype of T cell lymphoma, and NK/T cell lymphomas were more frequent than expected (5.4% of total). Hodgkin's lymphoma accounted for 12% of lymphoproliferative syndromes. Overall survival was greater than 90% at 2 years for indolent B cell lymphomas, and approximately 60% for DLBCL, somewhat lower than that previously reported. Survival was poor for PTCL-NOS and angioimmunoblastic T cell lymphoma, as expected; however, it was somewhat better than that in other studies for anaplastic large cell anaplastic lymphoma kinase lymphomas. This is the first prospective registry to report the frequencies, distribution, and survival of lymphomas in Spain. The frequencies and survival data we report here are globally consistent with that reported in other Western countries. These updated frequencies and survival statistics are necessary for developing appropriate management strategies for neoplasias in the Spanish population.
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http://dx.doi.org/10.1007/s00277-020-03918-6DOI Listing
April 2020
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